Contribution of aldosterone to cardiovascular and renal inflammation and fibrosis

Nature Reviews Nephrology

Volumn 9, Issue 8, 2013, Pages 459-469

  Brown, Nancy J ^a  

^a VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALDOSTERONE; ALDOSTERONE SYNTHASE; CORTICOSTERONE; EPLERENONE; GALECTIN 3; INTERLEUKIN 6; LCI 699; MINERALOCORTICOID RECEPTOR; NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE; NITRIC OXIDE; OSTEOPONTIN; OXYGENASE INHIBITOR; REACTIVE OXYGEN METABOLITE; TISSUE PLASMINOGEN ACTIVATOR; TRANSFORMING GROWTH FACTOR BETA1; UNCLASSIFIED DRUG;

ADOPTIVE TRANSFER; ALDOSTERONE BLOOD LEVEL; CARDITIS; DRUG MEGADOSE; FIBROSIS; HEART MUSCLE FIBROSIS; HORMONE RESPONSIVE ELEMENT; HUMAN; HYPERTENSION; KIDNEY FIBROSIS; MACROPHAGE; NEPHRITIS; NONHUMAN; OXIDATIVE STRESS; PLASMA RENIN ACTIVITY; PRIORITY JOURNAL; REVIEW; T LYMPHOCYTE ACTIVATION; TRANSACTIVATION;

ALDOSTERONE; ALDOSTERONE SYNTHASE; ANIMALS; AROMATASE INHIBITORS; CARDIOVASCULAR SYSTEM; ENDOTHELIAL CELLS; FADROZOLE; FIBROSIS; HUMANS; IMIDAZOLES; INFLAMMATION; KIDNEY; MACROPHAGES; MINERALOCORTICOID RECEPTOR ANTAGONISTS; MYOCARDIUM; MYOCYTES, CARDIAC; PYRIDINES; REACTIVE OXYGEN SPECIES; RECEPTORS, MINERALOCORTICOID; SODIUM, DIETARY;

EID: 84880922018     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2013.110     Document Type: Review

References (132)

1. Náray Fejes Tóth, A., Canessa, C., Cleaveland, E. S., Aldrich, G. & Fejes-Tóth, G. sgk is an aldosterone-induced kinase in the renal collecting duct. Effects on epithelial na+ channels. J. Biol. Chem. 274, 16973-16978 (1999
2. Snyder, P. M., Olson, D. R. & Thomas, B. C. Serum and glucocorticoid-regulated kinase modulates Nedd4 2 mediated inhibition of the epithelial Na+ channel. J. Biol. Chem. 277, 5-8 (2002
3. Bhalla, V., Soundararajan, R., Pao, A. C., Li, H. & Pearce, D. Disinhibitory pathways for control of sodium transport: Regulation of ENaC by SGK1 and GILZ. Am. J. Physiol. Renal Physiol. 291, F714-F721 (2006
4. Rozansky, D. J. et al. Aldosterone mediates activation of the thiazide-sensitive Na-Cl cotransporter through an SGK1 and WNK4 signaling pathway. J. Clin. Invest. 119, 2601-2612 (2009
5. Arroyo, J. P. et al. Nedd4-2 modulates renal Na+ Cl cotransporter via the aldosterone SGK1 Nedd4-2 pathway. J. Am. Soc. Nephrol. 22, 1707-1719 (2011
6. Sato, A. & Funder, J. W. High glucose stimulates aldosterone-induced hypertrophy via type I mineralocorticoid receptors in neonatal rat cardiomyocytes. Endocrinology 137, 4145-4153 (1996
7. Lombes, M. et al. Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor. Circ. Res. 71, 503-510 (1992
8. Terada, Y. et al. Aldosterone stimulates proliferation of mesangial cells by activating mitogen-activated protein kinase 1/2, cyclin D1, and cyclin A. J Am. Soc. Nephrol. 16, 2296-2305 (2005
9. Shibata, S., Nagase, M., Yoshida, S., Kawachi, H. & Fujita, T. Podocyte as the target for aldosterone: Roles of oxidative stress and Sgk1. Hypertension 49, 355-364 (2007
10. Guo, C. et al. Mineralocorticoid receptor blockade reverses obesity-related changes in expression of adiponectin, peroxisome proliferator-activated receptor-gamma, and proinflammatory adipokines. Circulation 117, 2253-2261 (2008
11. Calo, L. A. et al. Effect of aldosterone and glycyrrhetinic acid on the protein expression of PAI 1 and p22(phox) in human mononuclear leukocytes. J. Clin. Endocrinol. Metab 89, 1973-1976 (2004
12. Brilla, C. G. & Weber, K. T. Mineralocorticoid excess, dietary sodium, and myocardial fibrosis. J. Lab. Clin. Med. 120, 893-901 (1992
13. Lacolley, P. et al. Increased carotid wall elastic modulus and fibronectin in aldosterone salt treated rats effects of eplerenone. Circulation 106, 2848-2853 (2002
14. Greene, E. L., Kren, S. & Hostetter, T. H. Role of aldosterone in the remnant kidney model in the rat. J. Clin. Invest. 98, 1063-1068 (1996
15. Rocha, R. et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am. J. Physiol. Heart Circ. Physiol. 283, H1802-H1810 (2002
16. Blasi, E. R. et al. Aldosterone/salt induces renal inflammation and fibrosis in hypertensive rats. Kidney Int. 63, 1791-1800 (2003
17. Gerling, I. C. et al. Aldosteronism: An immunostimulatory state precedes proinflammatory/fibrogenic cardiac phenotype. Am. J. Physiol. Heart Circ. Physiol. 285, H813-H821 (2003
18. Brilla, C. G., Matsubara, L. S. & Weber, K. T. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J. Mol. Cell. Cardiol. 25, 563-575 (1993
19. Pitt, B. et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med. 341, 709-717 (1999
20. Zannad, F., Alla, F., Dousset, B., Perez, A. & Pitt, B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: Insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation 102, 2700-2706 (2000
21. Pitt, B. et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N. Engl. J. Med. 348, 1309-1321 (2003
22. Zannad, F. et al. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med. 364, 11-21 (2011
23. Volk, M. J., Bomback, A. S. & Klemmer, P. J. Mineralocorticoid receptor blockade in chronic kidney disease. Curr. Hypertens. Rep. 13, 282-288 (2011
24. Fiebeler, A. et al. Mineralocorticoid receptor affects AP 1 and nuclear factor-kappab activation in angiotensin II induced cardiac injury. Hypertension 37, 787-793 (2001
25. He, B. J. et al. Oxidation of CaMKII determines the cardiotoxic effects of aldosterone. Nat. Med. 17, 1610-1618 (2011
26. Keidar, S. et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: A possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation 109, 2213-2220 (2004
27. Iwashima, F. et al. Aldosterone induces superoxide generation via Rac1 activation in endothelial cells. Endocrinology 149, 1009-1014 (2008
28. Sun, Y. et al. Aldosterone-induced inflammation in the rat heart: Role of oxidative stress. Am. J. Pathol. 161, 1773-1781 (2002
29. Hirono, Y. et al. Angiotensin II receptor type 1-mediated vascular oxidative stress and proinflammatory gene expression in aldosterone-induced hypertension: The possible role of local renin-angiotensin system. Endocrinology 148, 1688-1696 (2007
30. Huang, S., Zhang, A., Ding, G. & Chen, R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am. J. Physiol. Renal Physiol. 296, F1323-F1333 (2009
31. Virdis, A., Neves, M. F., Amiri, F., Touyz, R. M. & Schiffrin, E. L. Role of NAD(P)H oxidase on vascular alterations in angiotensin II infused mice. J. Hypertens. 22, 535-542 (2004
32. Johar, S., Cave, A. C., Narayanapanicker, A., Grieve, D. J. & Shah, A. M. Aldosterone mediates angiotensin II induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J. 20, 1546-1548 (2006
33. Stas, S. et al. Mineralocorticoid receptor blockade attenuates chronic overexpression of the renin angiotensin aldosterone system stimulation of NADPH oxidase and cardiac remodeling. Endocrinology 148, 3773-3780 (2007
34. Matsui, H. et al. Salt excess causes left ventricular diastolic dysfunction in rats with metabolic disorder. Hypertension 52, 287-294 (2008
35. Yoshida, K. et al. Excess aldosterone under normal salt diet induces cardiac hypertrophy and infiltration via oxidative stress. Hypertens. Res. 28, 447-455 (2005
36. Rude, M. K. et al. Aldosterone stimulates matrix metalloproteinases and reactive oxygen species in adult rat ventricular cardiomyocytes. Hypertension 46, 555-561 (2005
37. Yuan, J., Jia, R. & Bao, Y. Aldosterone up-regulates production of plasminogen activator inhibitor 1 by renal mesangial cells. J. Biochem. Mol. Biol. 40, 180-188 (2007
38. Leopold, J. A. et al. Aldosterone impairs vascular reactivity by decreasing glucose 6 phosphate dehydrogenase activity. Nat. Med. 13, 189-197 (2007
39. Nagata, D. et al. Molecular mechanism of the inhibitory effect of aldosterone on endothelial NO synthase activity. Hypertension 48, 165-171 (2006
40. Oberleithner, H. et al. Plasma sodium stiffens vascular endothelium and reduces nitric oxide release. Proc. Natl Acad. Sci. USA 104, 16281-16286 (2007
41. Korte, S. et al. Firewall function of the endothelial glycocalyx in the regulation of sodium homeostasis. Pflugers Arch. 463, 269-278 (2012
42. Yuan, Y. et al. Mitochondrial dysfunction accounts for aldosterone-induced epithelial to mesenchymal transition of renal proximal tubular epithelial cells. Free Radic. Biol. Med. 53, 30-43 (2012
43. Zhang, A., Jia, Z., Guo, X. & Yang, T. Aldosterone induces epithelial-mesenchymal transition via ROS of mitochondrial origin. Am. J. Physiol. Renal Physiol. 293, F723-F731 (2007
44. Huang, S., Zhang, A., Ding, G. & Chen, R. Aldosterone-induced mesangial cell proliferation is mediated by EGF receptor transactivation. Am. J. Physiol. Renal Physiol. 296, F1323-F1333 (2009
45. Zhu, C. et al. Mitochondrial dysfunction mediates aldosterone-induced podocyte damage: A therapeutic target of PPARgamma. Am. J. Pathol. 178, 2020-2031 (2011
46. Zhang, A., Jia, Z., Wang, N., Tidwell, T. J. & Yang, T. Relative contributions of mitochondria and NADPH oxidase to deoxycorticosterone acetate-salt hypertension in mice. Kidney Int. 80, 51-60 (2011
47. Terada, Y. et al. Aldosterone stimulates nuclear factor-kappa B activity and transcription of intercellular adhesion molecule 1 and connective tissue growth factor in rat mesangial cells via serum-and glucocorticoid-inducible protein kinase 1. Clin. Exp. Nephrol. 16, 81-88 (2012
48. Leroy, V. et al. Aldosterone activates NF kappaB in the collecting duct. J. Am. Soc. Nephrol. 20, 131-144 (2009
49. Yang, M. et al. Serum-glucocorticoid regulated kinase 1 regulates alternatively activated macrophage polarization contributing to angiotensin II induced inflammation and cardiac fibrosis. Arterioscler. Thromb. Vasc. Biol. 32, 1675-1686 (2012
50. Artunc, F. et al. Blunted DOCA/high salt induced albuminuria and renal tubulointerstitial damage in gene-targeted mice lacking SGK1. J. Mol. Med. (Berl) 84, 737-746 (2006
51. Noble, N. A., Harper, J. R. & Border, W. A. In vivo interactions of TGF-beta and extracellular matrix. Prog. Growth Factor Res. 4, 369-382 (1992
52. Chun, T. Y., Bloem, L. J. & Pratt, J. H. Aldosterone inhibits inducible nitric oxide synthase in neonatal rat cardiomyocytes. Endocrinology 144, 1712-1717 (2003
53. Han, J. S., Choi, B. S., Yang, C. W. & Kim, Y. S. Aldosterone-induced TGF-beta1 expression is regulated by mitogen-activated protein kinases and activator protein 1 in mesangial cells. J. Korean Med. Sci. 24 (Suppl.), S195-S203 (2009
54. Juknevicius, I., Segal, Y., Kren, S., Lee, R. & Hostetter, T. H. Effect of aldosterone on renal transforming growth factor-beta. Am. J. Physiol. Renal Physiol. 286, F1059-F1062 (2004
55. Brown, N. J. et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor 1 production. J. Clin. Endocrinol. Metab. 85, 336-344 (2000
56. Chun, T. Y. & Pratt, J. H. Aldosterone increases plasminogen activator inhibitor 1 synthesis in rat cardiomyocytes. Mol. Cell Endocrinol. 239, 55-61 (2005
57. Huang, W. et al. Aldosterone and TGF-beta1 synergistically increase PAI 1 and decrease matrix degradation in rat renal mesangial and fibroblast cells. Am. J. Physiol. Renal Physiol. 294, F1287-F1295 (2008
58. Rerolle, J. P., Hertig, A., Nguyen, G., Sraer, J. D. & Rondeau, E. P. Plasminogen activator inhibitor type 1 is a potential target in renal fibrogenesis. Kidney Int. 58, 1841-1850 (2000
59. Ma, J. et al. Plasminogen activator inhibitor 1 deficiency protects against aldosterone-induced glomerular injury. Kidney Int. 69, 1064-1072 (2006
60. Oestreicher, E. M. et al. Aldosterone and not plasminogen activator inhibitor 1 is a critical mediator of early angiotensin II/NG nitro L- arginine methyl ester-induced myocardial injury. Circulation 108, 2517-2523 (2003
61. Weisberg, A. D. et al. Pharmacological inhibition and genetic deficiency of plasminogen activator inhibitor 1 attenuates angiotensin II/salt-induced aortic remodeling. Arterioscler. Thromb. Vasc. Biol. 25, 365-371 (2005
62. Ghosh, A. K. et al. Genetic deficiency of plasminogen activator inhibitor 1 promotes cardiac fibrosis in aged mice: Involvement of constitutive transforming growth factor-beta signaling and endothelial to mesenchymal transition. Circulation 122, 1200-1209 (2010
63. Moriwaki, H., Stempien-Otero, A., Kremen, M., Cozen, A. E. & Dichek, D. A. Overexpression of urokinase by macrophages or deficiency of plasminogen activator inhibitor type 1 causes cardiac fibrosis in mice. Circ. Res. 95, 637-644 (2004
64. Guarda, E., Katwa, L. C., Myers, P. R., Tyagi, S. C. & Weber, K. T. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc. Res. 27, 2130-2134 (1993
65. Park, J. B. & Schiffrin, E. L. Cardiac and vascular fibrosis and hypertrophy in aldosterone-infused rats: Role of endothelin 1. Am. J. Hypertens. 15, 164-169 (2002
66. Seccia, T. M. et al. Cardiac fibrosis occurs early and involves endothelin and AT 1 receptors in hypertension due to endogenous angiotensin II. J. Am. Coll. Cardiol. 41, 666-673 (2003
67. Tostes, R. C., Touyz, R. M., He, G., Ammarguellat, F. & Schiffrin, E. L. Endothelin A receptor blockade decreases expression of growth factors and collagen and improves matrix metalloproteinase 2 activity in kidneys from stroke-prone spontaneously hypertensive rats. J. Cardiovasc. Pharmacol. 39, 892-900 (2002
68. Stow, L. R. et al. Aldosterone modulates steroid receptor binding to the endothelin 1 gene (edn1). J. Biol. Chem. 284, 30087-30096 (2009
69. Jaffe, I. Z. et al. Placental growth factor mediates aldosterone- dependent vascular injury in mice. J. Clin. Invest. 120, 3891-3900 (2010
70. Isoda, K. et al. Osteopontin plays an important role in the development of medial thickening and neointimal formation. Circ. Res. 91, 77-82 (2002
71. Fu, G. X., Xu, C. C., Zhong, Y., Zhu, D. L. & Gao, P. J. Aldosterone-induced osteopontin expression in vascular smooth muscle cells involves MR, ERK, and p38 MAPK. Endocrine 42, 676-683 (2012
72. Sam, F. et al. Mice lacking osteopontin exhibit increased left ventricular dilation and reduced fibrosis after aldosterone infusion. Am. J. Hypertens. 17, 188-193 (2004
73. Irita, J. et al. Osteopontin deficiency protects against aldosterone-induced inflammation, oxidative stress, and interstitial fibrosis in the kidney. Am. J. Physiol. Renal Physiol. 301, F833-F844 (2011
74. Morrow, D. A. & O'Donoghue, M. L. Galectin 3 in cardiovascular disease: A possible window into early myocardial fibrosis. J. Am. Coll. Cardiol. 60, 1257-1258 (2012
75. Calvier, L. et al. Galectin 3 mediates aldosterone-induced vascular fibrosis. Arterioscler. Thromb. Vasc. Biol. 33, 67-75 (2013
76. Azibani, F. et al. Aldosterone inhibits antifibrotic factors in mouse hypertensive heart. Hypertension 59, 1179-1187 (2012
77. Kimura, K., Ohkita, M., Koyama, M. & Matsumura, Y. Reduced NO production rapidly aggravates renal function through the NF kappaB/ET 1/ETA receptor pathway in DOCA salt induced hypertensive rats. Life Sci. 91, 644-650 (2012
78. Ogawa, Y. et al. Natriuretic peptide receptor guanylyl cyclase A protects podocytes from aldosterone-induced glomerular injury. J. Am. Soc. Nephrol. 23, 1198-1209 (2012
79. Hellal-Levy, C., Fagart, J., Souque, A. & Rafestin-Oblin, M. E. Mechanistic aspects of mineralocorticoid receptor activation. Kidney Int. 57, 1250-1255 (2000
80. Christ, M., Meyer, C., Sippel, K. & Wehling, M. Rapid aldosterone signaling in vascular smooth muscle cells: Involvement of phospholipase C, diacylglycerol and protein kinase C alpha. Biochem. Biophys. Res. Commun. 213, 123-129 (1995
81. Min, L. J. et al. Aldosterone and angiotensin II synergistically induce mitogenic response in vascular smooth muscle cells. Circ. Res. 97, 434-442 (2005
82. Mazak, I. et al. Aldosterone potentiates angiotensin II induced signaling in vascular smooth muscle cells. Circulation 109, 2792-2800 (2004
83. Grossmann, C. et al. Aldosterone-induced EGFR expression: Interaction between the human mineralocorticoid receptor and the human EGFR promoter. Am. J. Physiol. Endocrinol. Metab. 292, E1790-E1800 (2007
84. Griol-Charhbili, V. et al. Epidermal growth factor receptor mediates the vascular dysfunction but not the remodeling induced by aldosterone/salt. Hypertension 57, 238-244 (2011
85. Messaoudi, S. et al. The epidermal growth factor receptor is involved in angiotensin II but not aldosterone/salt-induced cardiac remodelling. PLoS ONE 7, e30156 (2012
86. Sinphitukkul, K., Eiam-Ong, S., Manotham, K. & Eiam-Ong, S. Nongenomic effects of aldosterone on renal protein expressions of pEGFR and pERK1/2 in rat kidney. Am. J. Nephrol. 33, 111-120 (2011
87. De Giusti, V. C. et al. Aldosterone stimulates the cardiac Na(+)/H(+) exchanger via transactivation of the epidermal growth factor receptor. Hypertension 58, 912-919 (2011
88. Mihailidou, A S., Mardini, M. & Funder, J. W. Rapid, nongenomic effects of aldosterone in the heart mediated by epsilon protein kinase C. Endocrinology 145, 773-780 (2004
89. Li, R. C. et al. PKCepsilon modulates NF kappaB and AP 1 via mitogen-activated protein kinases in adult rabbit cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 279, H1679-H1689 (2000
90. Lemarie, C. A. et al. Aldosterone-induced activation of signaling pathways requires activity of angiotensin type 1a receptors. Circ. Res. 105, 852-859 (2009
91. McCurley, A. et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat. Med. 18, 1429-1433 (2012
92. Michea, L. et al. Eplerenone blocks nongenomic effects of aldosterone on the Na+/H+ exchanger, intracellular Ca2+ levels, and vasoconstriction in mesenteric resistance vessels. Endocrinology 146, 973-980 (2005
93. Haseroth, K. et al. Rapid nongenomic effects of aldosterone in mineralocorticoid receptor knockout mice. Biochem. Biophys. Res. Commun. 266, 257-261 (1999
94. Grossmann, C. et al. Human mineralocorticoid receptor expression renders cells responsive for nongenotropic aldosterone actions. Mol. Endocrinol. 19, 1697-1710 (2005
95. Gros, R. et al. GPR30 expression is required for the mineralocorticoid receptor-independent rapid vascular effects of aldosterone. Hypertension 57, 442-451 (2011
96. Batenburg, W. W., Jansen, P. M., van den Bogaerdt, A. J. & AH, J. D. Angiotensin II aldosterone interaction in human coronary microarteries involves GPR30, EGFR, and endothelial NO synthase. Cardiovasc. Res. 94, 136-143 (2012
97. Funder, J. W., Pearce, P. T., Smith, R. & Smith, A. I. Mineralocorticoid action: Target tissue specificity is enzyme, not receptor, mediated. Science 242, 583-585 (1988
98. Gong, R., Morris, D. J. & Brem, A. S. Variable expression of 11beta hydroxysteroid dehydrogenase (11beta-HSD) isoforms in vascular endothelial cells. Steroids 73, 1187-1196 (2008
99. Usher, M. G. et al. Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice. J. Clin. Invest 120, 3350-3364 (2010
100. Qin, W. et al. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ. Res. 93, 69-76 (2003
101. Lee, S. H. et al. Activation of local aldosterone system within podocytes is involved in apoptosis under diabetic conditions. Am. J. Physiol. Renal Physiol. 297, F1381-F1390 (2009
102. Terada, Y. et al. Aldosterone stimulates proliferation of mesangial cells by activating mitogen-activated protein kinase 1/2, cyclin d1, and cyclin a. J. Am. Soc. Nephrol. 16, 2296-2305 (2005
103. Mihailidou, A. S., Loan Le, T. Y., Mardini, M. & Funder, J. W. Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction. Hypertension 54, 1306-1312 (2009
104. Rickard, A J., Funder, J. W., Morgan, J., Fuller, P. J. & Young, M. J. Does glucocorticoid receptor blockade exacerbate tissue damage after mineralocorticoid/salt administration? Endocrinology 148, 4829-4835 (2007
105. Young, M. J., Morgan, J., Brolin, K., Fuller, P. J. & Funder, J. W. Activation of mineralocorticoid receptors by exogenous glucocorticoids and the development of cardiovascular inflammatory responses in adrenalectomized rats. Endocrinology 151, 2622-2628 (2010
106. Shibata, S. et al. Modification of mineralocorticoid receptor function by Rac1 GTPase: Implication in proteinuric kidney disease. Nat. Med. 14, 1370-1376 (2008
107. Shibata, S. et al. Rac1 GTPase in rodent kidneys is essential for salt-sensitive hypertension via a mineralocorticoid receptor-dependent pathway. J. Clin. Invest 121, 3233-3243 (2011
108. Kawarazaki, W. et al. Angiotensin II and salt-induced kidney injury through Rac1-mediated mineralocorticoid receptor activation. J. Am. Soc. Nephrol. 23, 997-1007 (2012
109. Nagase, M. et al. Oxidative stress causes mineralocorticoid receptor activation in rat cardiomyocytes: Role of small GTPase Rac1. Hypertension 59, 500-506 (2012
110. Oki, K., Gomez-Sanchez, E. P. & Gomez-Sanchez, C. E. Role of mineralocorticoid action in the brain in salt-sensitive hypertension. Clin. Exp. Pharmacol. Physiol 39, 90-95 (2012
111. Fraccarollo, D. et al. Deletion of cardiomyocyte mineralocorticoid receptor ameliorates adverse remodeling after myocardial infarction. Circulation 123, 400-408 (2011
112. Lother, A. et al. Ablation of mineralocorticoid receptors in myocytes but not in fibroblasts preserves cardiac function. Hypertension 57, 746-754 (2011
113. Rickard, A. J. et al. Deletion of mineralocorticoid receptors from macrophages protects against deoxycorticosterone/salt-induced cardiac fibrosis and increased blood pressure. Hypertension 54, 537-543 (2009
114. Bienvenu, L. A. et al. Macrophage mineralocorticoid receptor signaling plays a key role in aldosterone-independent cardiac fibrosis. Endocrinology 153, 3416-3425 (2012
115. Caprio, M. et al. Functional mineralocorticoid receptors in human vascular endothelial cells regulate intercellular adhesion molecule 1 expression and promote leukocyte adhesion. Circ. Res. 102, 1359-1367 (2008
116. Jeong, Y. et al. Aldosterone activates endothelial exocytosis. Proc. Natl Acad. Sci. USA 106, 3782-3787 (2009
117. Guzik, T. J. et al. Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. J. Exp. Med. 204, 2449-2460 (2007
118. Vinh, A. et al. Inhibition and genetic ablation of the B7/CD28 T cell costimulation axis prevents experimental hypertension. Circulation 122, 2529-2537 (2010
119. Herrada, A. A. et al. Aldosterone promotes autoimmune damage by enhancing Th17-mediated immunity. J. Immunol. 184, 191-202 (2010
120. Kasal, D. A. et al. T regulatory lymphocytes prevent aldosterone-induced vascular injury. Hypertension 59, 324-330 (2012
121. Messaoudi, S. et al. Aldosterone-specific activation of cardiomyocyte mineralocorticoid receptor in vivo. Hypertension 61, 361-367 (2013
122. Lee, G. et al. Homeostatic responses in the adrenal cortex to the absence of aldosterone in mice. Endocrinology 146, 2650-2656 (2005
123. Makhanova, N. et al. Kidney function in mice lacking aldosterone. Am. J. Physiol. Renal Physiol. 290, F61-F69 (2006
124. Luther, J. M. et al. Aldosterone deficiency and mineralocorticoid receptor antagonism prevent angiotensin II induced cardiac, renal, and vascular injury. Kidney Int. 82, 643-651 (2012
125. Rafiq, K. et al. Effects of mineralocorticoid receptor blockade on glucocorticoid-induced renal injury in adrenalectomized rats. J. Hypertens. 29, 290-298 (2011
126. Fiebeler, A. et al. Aldosterone synthase inhibitor ameliorates angiotensin II induced organ damage. Circulation 111, 3087-3094 (2005
127. Fiebeler, A. et al. Aldosterone synthase inhibitor FAD286 ameliorates angiotensin II induced end-organ damage. Hypertension 44, 514-515 (2004
128. Gamliel-Lazarovich, A. et al. FAD286, an aldosterone synthase inhibitor, reduced atherosclerosis and inflammation in apolipoprotein E deficient mice. J. Hypertens. 28, 1900-1907 (2010
129. Amar, L. et al. Aldosterone synthase inhibition with LCI699: A proof of concept study in patients with primary aldosteronism. Hypertension 56, 831-838 (2010
130. Amar, L., Azizi, M., Menard, J., Peyrard, S. & Plouin, P. F. Sequential comparison of aldosterone synthase inhibition and mineralocorticoid blockade in patients with primary aldosteronism. J. Hypertens. 31, 624-629 (2013
131. Calhoun, D. A. et al. Effects of a novel aldosterone synthase inhibitor for treatment of primary hypertension: Results of a randomized, double-blind, placebo-and active-controlled phase 2 trial. Circulation 124, 1945-1955 (2011
132. Azizi, M., Amar, L. & Menard, J. Aldosterone synthase inhibition in humans. Nephrol. Dial. Transplant. 28, 36-43 (2013